Association of cardiometabolic and genetic risk with incidence of dementia
Authors: Panagiota Kontari
Journal: The Lancet Healthy Longevity (2022)

In The Lancet Healthy Longevity Xin You Tai and colleagues1Tai XY Veldsman M Lyall DM et al.Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study.Lancet Healthy Longev. 2022; 3: e428-e436Summary Full Text Full Text PDF Scopus (1) Google Scholar examined the association between cardiometabolic multimorbidity and dementia risk, as well as the potential interaction with polygenic risk, in a large sample of older adults of European ancestry.The main finding of this study was that cardiometabolic multimorbidity and genetic risk are independently associated with dementia incidence and that cardiometabolic multimorbidity was associated with more widespread structural changes in the brain. Specifically, participants with multiple cardiometabolic conditions, including stroke, diabetes, and myocardial infarction, had a greater risk of developing dementia; however, this relationship was not significantly modified by genetic risk. Cardiometabolic multimorbidity was associated with lower total hippocampal and grey matter volumes and with higher white matter hyperintensity volume, whereas polygenic risk was associated with lower hippocampal volume only. 1Tai XY Veldsman M Lyall DM et al.Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study.Lancet Healthy Longev. 2022; 3: e428-e436Summary Full Text Full Text PDF Scopus (1) Google ScholarIn recent years, many epidemiological studies have focused on the potential additive effects of co-occurring cardiometabolic conditions on dementia incidence; however, the evidence is unclear, with some studies reporting that cardiometabolic conditions, both individually and jointly, are associated with increased risk of dementia, whereas other studies report no association.2Atti AR Valente S Iodice A et al.Metabolic syndrome, mild cognitive impairment, and dementia: a meta-analysis of longitudinal studies.Am J Geriatr Psychiatry. 2019; 27: 625-637Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 3Shaaban CE Jia Y Chang CH Ganguli M Independent and joint effects of vascular and cardiometabolic risk factor pairs for risk of all-cause dementia: a prospective population-based study.Int Psychogeriatr. 2019; 31: 1421-1432Crossref PubMed Scopus (11) Google ScholarIn the context of increasing prevalence of both dementia and cardiometabolic multimorbidity,4Nichols E Steinmetz JD Vollset SE et al.Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019.Lancet Public Health. 2022; 7: e105-e125Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 5Bell SP Saraf AA Epidemiology of multimorbidity in older adults with cardiovascular disease.Clin Geriatr Med. 2016; 32: 215-226Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Tai and colleagues' findings contribute to the literature by addressing an important question about how cardiometabolic multimorbidity of stroke, myocardial infarction, and diabetes, combined with genetic risk, are linked to dementia incidence and structural brain health. Methodologically, this study benefitted from the use of a large sample from a well established longitudinal cohort (the UK Biobank) that has been previously used to investigate risk factors for dementia. The novelty of this study is the examination of both multiple cardiometabolic conditions and a comprehensive polygenic risk score in relation to dementia risk and associated neuroimaging features. Through the prospective design, the use of population-based health and genetic data, and the use of brain imaging measures, Tai and colleagues achieved a holistic approach in the investigation of dementia risk.Nonetheless, some limitations need to be raised. First, missingness might cause selection bias, which might have resulted in an underestimation of the effects of risk factors on dementia and brain health outcomes. Second, cardiometabolic multimorbidity was determined on the basis of three cardiometabolic conditions only and by using a cardiometabolic risk score approach, which quantifies conditions but overlooks the pattern of combinations.Within the context of these limitations, future research needs to extend these findings by exploring whether the co-occurrence of additional cardiometabolic disorders, such as hypertension, obesity, and high blood glucose, triglycerides, and cholesterol, predicts dementia risk, as has been previously suggested by other studies. For example, hyperglycaemia6Neergaard JS Dragsbæk K Christiansen C et al.Metabolic syndrome, insulin resistance, and cognitive dysfunction: does your metabolic profile affect your brain?.Diabetes. 2017; 66: 1957-1963Crossref PubMed Scopus (46) Google Scholar and hypertension7Ou YN Tan CC Shen XN et al.Blood pressure and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 209 prospective studies.Hypertension. 2020; 76: 217-225Crossref PubMed Scopus (61) Google Scholar have been consistently associated with an increased risk of dementia, whereas heterogeneous results have been shown for the association of dyslipidaemia and obesity with dementia risk.8Ma Y Ajnakina O Steptoe A Cadar D Higher risk of dementia in English older individuals who are overweight or obese.Int J Epidemiol. 2020; 49: 1353-1365Crossref PubMed Scopus (40) Google Scholar, 9Mielke MM Zandi PP Sjögren M et al.High total cholesterol levels in late life associated with a reduced risk of dementia.Neurology. 2005; 64: 1689-1695Crossref PubMed Scopus (312) Google Scholar Given that cardiometabolic and genetic risk factors tend to co-occur among older individuals,5Bell SP Saraf AA Epidemiology of multimorbidity in older adults with cardiovascular disease.Clin Geriatr Med. 2016; 32: 215-226Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar it might be useful for future research to assess whether the combination of cardiometabolic and genetic risk factors has any synergistic effect on dementia, and which combination might be more predictive of developing subsequent dementia.The findings of Tai and colleagues' study highlight a continued need for longitudinal repeated-measures studies to shed light on the complex aetiology of dementia and to elucidate the inter-related effects of potential risk factors. Also, future studies should build on previous efforts to investigate the shared causes of cardiometabolic disorders and dementia-related diseases—eg, through analysis of the shared genetic basis for these conditions.Furthermore, given the cross-cultural differences in the prevalence of cardiometabolic conditions and evidence of substantial changes in disease burden, with a rapid increase in cardiovascular diseases, in low-income and middle-income countries,10Hu P Lee J Beaumaster S et al.Cognitive Function and Cardiometabolic-Inflammatory Risk Factors Among Older Indians and Americans.J Am Geriatr Soc. 2020; 68: S36-S44PubMed Google Scholar further investigation of the inter-relationship of cardiometabolic and genetic factors with the risk of dementia across different countries should be considered.Overall, the findings from this study show that the association of cardiometabolic multimorbidity with dementia incidence is greater than, and independent of, genetic risk, highlighting the importance of risk factor modification for every individual regardless of predetermined genetic factors. These findings have important implications for clinical and public health practice. This research could inform future dementia prevention strategies and could support the development of tailored health policies for dementia in the general population, by targeting those with high cardiometabolic risk regardless of genetic predisposition. In The Lancet Healthy Longevity Xin You Tai and colleagues1Tai XY Veldsman M Lyall DM et al.Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study.Lancet Healthy Longev. 2022; 3: e428-e436Summary Full Text Full Text PDF Scopus (1) Google Scholar examined the association between cardiometabolic multimorbidity and dementia risk, as well as the potential interaction with polygenic risk, in a large sample of older adults of European ancestry. The main finding of this study was that cardiometabolic multimorbidity and genetic risk are independently associated with dementia incidence and that cardiometabolic multimorbidity was associated with more widespread structural changes in the brain. Specifically, participants with multiple cardiometabolic conditions, including stroke, diabetes, and myocardial infarction, had a greater risk of developing dementia; however, this relationship was not significantly modified by genetic risk. Cardiometabolic multimorbidity was associated with lower total hippocampal and grey matter volumes and with higher white matter hyperintensity volume, whereas polygenic risk was associated with lower hippocampal volume only. 1Tai XY Veldsman M Lyall DM et al.Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study.Lancet Healthy Longev. 2022; 3: e428-e436Summary Full Text Full Text PDF Scopus (1) Google Scholar In recent years, many epidemiological studies have focused on the potential additive effects of co-occurring cardiometabolic conditions on dementia incidence; however, the evidence is unclear, with some studies reporting that cardiometabolic conditions, both individually and jointly, are associated with increased risk of dementia, whereas other studies report no association.2Atti AR Valente S Iodice A et al.Metabolic syndrome, mild cognitive impairment, and dementia: a meta-analysis of longitudinal studies.Am J Geriatr Psychiatry. 2019; 27: 625-637Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 3Shaaban CE Jia Y Chang CH Ganguli M Independent and joint effects of vascular and cardiometabolic risk factor pairs for risk of all-cause dementia: a prospective population-based study.Int Psychogeriatr. 2019; 31: 1421-1432Crossref PubMed Scopus (11) Google Scholar In the context of increasing prevalence of both dementia and cardiometabolic multimorbidity,4Nichols E Steinmetz JD Vollset SE et al.Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019.Lancet Public Health. 2022; 7: e105-e125Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 5Bell SP Saraf AA Epidemiology of multimorbidity in older adults with cardiovascular disease.Clin Geriatr Med. 2016; 32: 215-226Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Tai and colleagues' findings contribute to the literature by addressing an important question about how cardiometabolic multimorbidity of stroke, myocardial infarction, and diabetes, combined with genetic risk, are linked to dementia incidence and structural brain health. Methodologically, this study benefitted from the use of a large sample from a well established longitudinal cohort (the UK Biobank) that has been previously used to investigate risk factors for dementia. The novelty of this study is the examination of both multiple cardiometabolic conditions and a comprehensive polygenic risk score in relation to dementia risk and associated neuroimaging features. Through the prospective design, the use of population-based health and genetic data, and the use of brain imaging measures, Tai and colleagues achieved a holistic approach in the investigation of dementia risk. Nonetheless, some limitations need to be raised. First, missingness might cause selection bias, which might have resulted in an underestimation of the effects of risk factors on dementia and brain health outcomes. Second, cardiometabolic multimorbidity was determined on the basis of three cardiometabolic conditions only and by using a cardiometabolic risk score approach, which quantifies conditions but overlooks the pattern of combinations. Within the context of these limitations, future research needs to extend these findings by exploring whether the co-occurrence of additional cardiometabolic disorders, such as hypertension, obesity, and high blood glucose, triglycerides, and cholesterol, predicts dementia risk, as has been previously suggested by other studies. For example, hyperglycaemia6Neergaard JS Dragsbæk K Christiansen C et al.Metabolic syndrome, insulin resistance, and cognitive dysfunction: does your metabolic profile affect your brain?.Diabetes. 2017; 66: 1957-1963Crossref PubMed Scopus (46) Google Scholar and hypertension7Ou YN Tan CC Shen XN et al.Blood pressure and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 209 prospective studies.Hypertension. 2020; 76: 217-225Crossref PubMed Scopus (61) Google Scholar have been consistently associated with an increased risk of dementia, whereas heterogeneous results have been shown for the association of dyslipidaemia and obesity with dementia risk.8Ma Y Ajnakina O Steptoe A Cadar D Higher risk of dementia in English older individuals who are overweight or obese.Int J Epidemiol. 2020; 49: 1353-1365Crossref PubMed Scopus (40) Google Scholar, 9Mielke MM Zandi PP Sjögren M et al.High total cholesterol levels in late life associated with a reduced risk of dementia.Neurology. 2005; 64: 1689-1695Crossref PubMed Scopus (312) Google Scholar Given that cardiometabolic and genetic risk factors tend to co-occur among older individuals,5Bell SP Saraf AA Epidemiology of multimorbidity in older adults with cardiovascular disease.Clin Geriatr Med. 2016; 32: 215-226Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar it might be useful for future research to assess whether the combination of cardiometabolic and genetic risk factors has any synergistic effect on dementia, and which combination might be more predictive of developing subsequent dementia. The findings of Tai and colleagues' study highlight a continued need for longitudinal repeated-measures studies to shed light on the complex aetiology of dementia and to elucidate the inter-related effects of potential risk factors. Also, future studies should build on previous efforts to investigate the shared causes of cardiometabolic disorders and dementia-related diseases—eg, through analysis of the shared genetic basis for these conditions. Furthermore, given the cross-cultural differences in the prevalence of cardiometabolic conditions and evidence of substantial changes in disease burden, with a rapid increase in cardiovascular diseases, in low-income and middle-income countries,10Hu P Lee J Beaumaster S et al.Cognitive Function and Cardiometabolic-Inflammatory Risk Factors Among Older Indians and Americans.J Am Geriatr Soc. 2020; 68: S36-S44PubMed Google Scholar further investigation of the inter-relationship of cardiometabolic and genetic factors with the risk of dementia across different countries should be considered. Overall, the findings from this study show that the association of cardiometabolic multimorbidity with dementia incidence is greater than, and independent of, genetic risk, highlighting the importance of risk factor modification for every individual regardless of predetermined genetic factors. These findings have important implications for clinical and public health practice. This research could inform future dementia prevention strategies and could support the development of tailored health policies for dementia in the general population, by targeting those with high cardiometabolic risk regardless of genetic predisposition. I declare no competing interests. Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort studyCardiometabolic multimorbidity was independently associated with the risk of dementia and extensive brain imaging differences to a greater extent than was genetic risk. Targeting cardiometabolic multimorbidity might help to reduce the risk of dementia, regardless of genetic risk. Full-Text PDF Open Access